NRF2 activates a partial epithelial-mesenchymal transition and is maximally present in a hybrid epithelial/mesenchymal phenotype.
Antigens, CD
/ metabolism
Cadherins
/ metabolism
Carcinoma, Non-Small-Cell Lung
/ metabolism
Cell Adhesion
Cell Line, Tumor
Cell Movement
Epithelial Cells
Epithelial-Mesenchymal Transition
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Humans
Kaplan-Meier Estimate
Lung Neoplasms
/ metabolism
Models, Theoretical
NF-E2-Related Factor 2
/ metabolism
Neoplasm Metastasis
Neoplastic Cells, Circulating
Phenotype
Prognosis
Urinary Bladder Neoplasms
/ metabolism
Zinc Finger E-box-Binding Homeobox 1
/ metabolism
Journal
Integrative biology : quantitative biosciences from nano to macro
ISSN: 1757-9708
Titre abrégé: Integr Biol (Camb)
Pays: England
ID NLM: 101478378
Informations de publication
Date de publication:
01 06 2019
01 06 2019
Historique:
received:
18
12
2018
revised:
10
05
2019
accepted:
11
06
2019
pubmed:
23
7
2019
medline:
18
3
2020
entrez:
23
7
2019
Statut:
ppublish
Résumé
The epithelial-mesenchymal transition (EMT) is a key process implicated in cancer metastasis and therapy resistance. Recent studies have emphasized that cells can undergo partial EMT to attain a hybrid epithelial/mesenchymal (E/M) phenotype - a cornerstone of tumour aggressiveness and poor prognosis. These cells can have enhanced tumour-initiation potential as compared to purely epithelial or mesenchymal ones and can integrate the properties of cell-cell adhesion and motility that facilitates collective cell migration leading to clusters of circulating tumour cells (CTCs) - the prevalent mode of metastasis. Thus, identifying the molecular players that can enable cells to maintain a hybrid E/M phenotype is crucial to curb the metastatic load. Using an integrated computational-experimental approach, we show that the transcription factor NRF2 can prevent a complete EMT and instead stabilize a hybrid E/M phenotype. Knockdown of NRF2 in hybrid E/M non-small cell lung cancer cells H1975 and bladder cancer cells RT4 destabilized a hybrid E/M phenotype and compromised the ability to collectively migrate to close a wound in vitro. Notably, while NRF2 knockout simultaneously downregulated E-cadherin and ZEB-1, overexpression of NRF2 enriched for a hybrid E/M phenotype by simultaneously upregulating both E-cadherin and ZEB-1 in individual RT4 cells. Further, we predict that NRF2 is maximally expressed in hybrid E/M phenotype(s) and demonstrate that this biphasic dynamic arises from the interconnections among NRF2 and the EMT regulatory circuit. Finally, clinical records from multiple datasets suggest a correlation between a hybrid E/M phenotype, high levels of NRF2 and its targets and poor survival, further strengthening the emerging notion that hybrid E/M phenotype(s) may occupy the 'metastatic sweet spot'.
Identifiants
pubmed: 31329868
pii: 5536973
doi: 10.1093/intbio/zyz021
pmc: PMC6686740
doi:
Substances chimiques
Antigens, CD
0
CDH1 protein, human
0
Cadherins
0
NF-E2-Related Factor 2
0
NFE2L2 protein, human
0
ZEB1 protein, human
0
Zinc Finger E-box-Binding Homeobox 1
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
251-263Subventions
Organisme : NCI NIH HHS
ID : F30 CA213878
Pays : United States
Informations de copyright
© The Author(s) 2019. Published by Oxford University Press.
Références
Proc Natl Acad Sci U S A. 2009 Apr 28;106(17):7010-5
pubmed: 19372377
Integr Biol (Camb). 2014 Feb;6(2):192-202
pubmed: 24336811
Oncogene. 2010 Jun 17;29(24):3490-500
pubmed: 20418909
Asian J Androl. 2016 Sep-Oct;18(5):704-10
pubmed: 27427552
Oncotarget. 2016 May 10;7(19):27067-84
pubmed: 27008704
Mol Cell Proteomics. 2012 Mar;11(3):O111.009613
pubmed: 21964433
Free Radic Biol Med. 2015 Nov;88(Pt B):147-157
pubmed: 25937177
Nature. 2018 Apr;556(7702):463-468
pubmed: 29670281
Science. 2016 Apr 8;352(6282):167-9
pubmed: 27124449
Science. 2011 Feb 11;331(6018):764-8
pubmed: 21233346
Cancer Res. 2017 Nov 15;77(22):6415-6428
pubmed: 28947416
Cancer Res. 2019 Nov 1;79(21):5527-5535
pubmed: 31481500
Carcinogenesis. 2008 Jun;29(6):1235-43
pubmed: 18413364
Front Oncol. 2015 Jul 20;5:155
pubmed: 26258068
Chronic Dis Transl Med. 2015 Oct 22;1(3):175-186
pubmed: 29063005
Genes Dev. 2013 Oct 15;27(20):2179-91
pubmed: 24142871
BMC Pharmacol Toxicol. 2018 Apr 2;19(1):13
pubmed: 29609658
PLoS Genet. 2017 Apr 28;13(4):e1006762
pubmed: 28453520
NPJ Breast Cancer. 2017 Jun 6;3:21
pubmed: 28649661
Sci Rep. 2016 Dec 16;6:38646
pubmed: 27982105
Oncotarget. 2015 Jun 20;6(17):15436-48
pubmed: 25944618
Cell Death Dis. 2018 Jan 23;9(2):83
pubmed: 29362432
Sci Transl Med. 2016 Apr 13;8(334):334ra51
pubmed: 27075625
BMC Cancer. 2015 Jul 21;15:531
pubmed: 26194347
Oncotarget. 2016 Nov 8;7(45):73593-73606
pubmed: 27713154
Genes Dev. 2008 Apr 1;22(7):894-907
pubmed: 18381893
PLoS One. 2013 Oct 04;8(10):e76773
pubmed: 24124593
Food Chem Toxicol. 1999 Sep-Oct;37(9-10):973-9
pubmed: 10541453
J Cell Biochem. 2017 Sep;118(9):2559-2570
pubmed: 28266048
Oncotarget. 2018 Jul 6;9(52):29906-29920
pubmed: 30042822
Nucleic Acids Res. 2012 Aug;40(15):7416-29
pubmed: 22581777
BMC Cancer. 2014 Dec 17;14:970
pubmed: 25518851
J Clin Med. 2019 May 22;8(5):
pubmed: 31121840
Cancer Res. 2014 Feb 1;74(3):808-17
pubmed: 24322982
Trends Biochem Sci. 2014 Apr;39(4):199-218
pubmed: 24647116
PLoS Comput Biol. 2017 Mar 31;13(3):e1005456
pubmed: 28362798
Oxid Med Cell Longev. 2016;2016:2428153
pubmed: 26682001
Cell Metab. 2018 Jul 03;28(1):69-86.e6
pubmed: 29972798
Cancer Res. 2015 Sep 15;75(18):3925-35
pubmed: 26292362
J Biol Chem. 2011 Nov 25;286(47):40725-33
pubmed: 21926171
Oncogene. 2010 Jun 24;29(25):3703-14
pubmed: 20440267
PLoS One. 2015 May 28;10(5):e0126522
pubmed: 26020648
Dev Cell. 2014 Apr 14;29(1):59-74
pubmed: 24735879
Dis Markers. 2016;2016:8143465
pubmed: 27999449
J Cell Sci. 2012 Mar 1;125(Pt 5):1284-95
pubmed: 22302998
PLoS One. 2015 Jul 30;10(7):e0132978
pubmed: 26226105
Proc Natl Acad Sci U S A. 2019 Jan 2;116(1):148-157
pubmed: 30587589
PLoS Comput Biol. 2015 Nov 10;11(11):e1004569
pubmed: 26554584
Proc Natl Acad Sci U S A. 2013 Nov 5;110(45):18144-9
pubmed: 24154725
Sci Rep. 2018 Jun 7;8(1):8704
pubmed: 29880891
J R Soc Interface. 2017 Nov;14(136):
pubmed: 29187638
World Neurosurg. 2013 Sep-Oct;80(3-4):363-70
pubmed: 22120303
J R Soc Interface. 2014 Dec 6;11(101):20140962
pubmed: 25339690